title: Progesterone receptor membrane component 1/Sigma-2 receptor associates with MAP1LC3B and promotes autophagy.
abstract: Autophagy resembles a recycling process in which proteins, organelles, or regions of the cytoplasm are enveloped and degraded. We have found that two of the central autophagy proteins, MAP1LC3 (microtubule-associated protein 1 light chain 3, also described as LC3) and UVRAG (UV radiation resistance associated/UV radiation associated gene), complex with PGRMC1/S2R (progesterone receptor membrane component 1, also known as sigma-2 receptor). PGRMC1 is a cytochrome that is induced in cancer and is essential for tumor formation, invasion, and metastasis. Autophagy contributes to the turnover of long-lived and/or ubiquitinated proteins and the clearance of damaged organelles, and we have shown that PGRMC1 promotes both processes. Inhibition of PGRMC1 by RNAi or small molecule inhibitors causes autophagy substrates to increase and aberrant mitochondria to accumulate. We propose that this disruption of autophagy upon PGRMC1 inhibition increases AMPK activation, elevating the levels of TSC1 (tuberous sclerosis complex) and TSC2 and inactivating MTOR and RPS6KB/p70S6K, causing cleaved MAP1LC3B levels to increase. Thus, PGRMC1 binds to key components of the autophagy machinery and is required for the degradative activity of autophagy.
authors.affiliation: Department of Molecular and Biomedical Pharmacology; Markey Cancer Center; University of Kentucky; Lexington, KY USA.
authors.forename: Shakeel U R
authors.initials: SU
authors.lastname: Mir
authors.affiliation: Department of Molecular and Biomedical Pharmacology; Markey Cancer Center; University of Kentucky; Lexington, KY USA.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Schwarze
authors.affiliation: Department of Molecular and Biomedical Pharmacology; Markey Cancer Center; University of Kentucky; Lexington, KY USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Jin
authors.affiliation: Department of Molecular and Biomedical Pharmacology; Markey Cancer Center; University of Kentucky; Lexington, KY USA.
authors.forename: Jinling
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Molecular and Biomedical Pharmacology; Markey Cancer Center; University of Kentucky; Lexington, KY USA.
authors.forename: Woodrow
authors.initials: W
authors.lastname: Friend
authors.affiliation: Department of Toxicology; Markey Cancer Center; University of Kentucky; Lexington, KY USA.
authors.forename: Sumitra
authors.initials: S
authors.lastname: Miriyala
authors.affiliation: Department of Toxicology; Markey Cancer Center; University of Kentucky; Lexington, KY USA.
authors.forename: Daret
authors.initials: D
authors.lastname: St Clair
authors.affiliation: Department of Molecular and Biomedical Pharmacology; Markey Cancer Center; University of Kentucky; Lexington, KY USA.
authors.forename: Rolf J
authors.initials: RJ
authors.lastname: Craven
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D059748:Proteolysis; D011980:Receptors, Progesterone / Q000187:drug effects / Q000378:metabolism*; D017480:Receptors, sigma / Q000187:drug effects / Q000378:metabolism*; D000071456:Sequestosome-1 Protein; D014402:Tuberous Sclerosis / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C502070:MAP1LC3B protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D011980:Receptors, Progesterone; D017480:Receptors, sigma; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; C106107:sigma-2 receptor; D055372:AMP-Activated Protein Kinases
keywords: TOR; autophagy; metabolism; therapeutics; ubiquitin